This application is a 371 of PCT/GB00/03314, filed Aug. 30, 2000.
The present invention relates to compounds which elevate pyruvate dehydrogenase (PDH) activity, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with reduced PDH activity, to their use as medicaments and to their use in the manufacture of medicaments for use in the elevation of PDH activity in warm-blooded animals such as humans, in particular the treatment of diabetes mellitus, peripheral vascular disease and myocardial ischaemia in warm-blooded animals such as humans, more particularly to their use in the manufacture of medicaments for use in the treatment of diabetes mellitus in warm-blooded animals such as humans.
Within tissues adenosine triphosphate (ATP) provides the energy for synthesis of complex molecules and, in muscle, for contraction. ATP is generated from the breakdown of energy-rich substrates such as glucose or long chain free fatty acids. In oxidative tissues such as muscle the majority of the ATP is generated from acetyl CoA which enters the citric acid cycle, thus the supply of acetyl CoA is a critical determinant of ATP production in oxidative tissues. Acetyl CoA is produced either by xcex2-oxidation of fatty acids or as a result of glucose metabolism by the glycolytic pathway. The key regulatory enzyme in controlling the rate of acetyl CoA formation from glucose is PDH which catalyses the oxidation of pyruvate to acetyl CoA and carbon dioxide with concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH.
In disease states such as both non-insulin dependent (NIDDM) and insulin-dependent diabetes mellitus (IDDM), oxidation of lipids is increased with a concomitant reduction in utilisation of glucose, which contributes to the hyperglycaemia. Reduced glucose utilisation in both IDDM and NIDDM is associated with a reduction in PDH activity. In addition, a further consequence of reduced PDH activity may be that an increase in pyruvate concentration results in increased availability of lactate as a substrate for hepatic gluconeogenesis. It is reasonable to expect that increasing the activity of PDH could increase the rate of glucose oxidation and hence overall glucose utilisation, in addition to reducing hepatic glucose output. Another factor contributing to diabetes mellitus is impaired insulin secretion, which has been shown to be associated with reduced PDH activity in pancreatic xcex2-cells (in a rodent genetic model of diabetes mellitus Zhou et al. (1996) Diabetes 45: 580-586).
Oxidation of glucose is capable of yielding more molecules of ATP per mole of oxygen than is oxidation of fatty acids. In conditions where energy demand may exceed energy supply, such as myocardial ischaemia, intermittent claudication, cerebral ischaemia and reperfusion, (Zaidan et al., 1998; J. Neurochem. 70: 233-241), shifting the balance of substrate utilisation in favour of glucose metabolism by elevating PDH activity may be expected to improve the ability to maintain ATP levels and hence function.
An agent which is capable of elevating PDH activity may also be expected to be of benefit in treating conditions where an excess of circulating lactic acid is manifest such as in certain cases of sepsis.
The agent dichloroacetic acid (DCA) which increases the activity of PDH after acute administration in animals, (Vary et al., 1988; Circ. Shock, 24: 3-18), has been shown to have the predicted effects in reducing glycaemia, (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530), and as a therapy for myocardial ischaemia (Bersin and Stacpoole 1997; American Heart Journal, 134: 841-855) and lactic acidaemia, (Stacpoole et al., 1983; N. Engl. J. Med. 309: 390-396).
PDH is an intramitochondrial multienzyme complex consisting of multiple copies of several subunits including three enzyme activities E1, E2 and E3, required for the completion of the conversion of pyruvate to acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). E1 catalyses the non-reversible removal of CO2 from pyruvate; E2 forms acetyl CoA and E3 reduces NAD to NADH. Two additional enzyme activities are associated with the complex: a specific kinase which is capable of phosphorylating E1 at three serine residues and a loosely-associated specific phosphatase which reverses the phosphorylation. Phosphorylation of a single one of the three serine residues renders the E1 inactive. The proportion of the PDH in its active (dephosphorylated) state is determined by a balance between the activity of the kinase and phosphatase. The activity of the kinase may be regulated in vivo by the relative concentrations of metabolic substrates such as NAD/NADH, CoA/acetylCoA and adenine diphosphate (ADP)/ATP as well as by the availability of pyruvate itself.
European Patent Publication Nos. 617010 and 524781 describes compounds which are capable of relaxing bladder smooth muscle and which may be used in the treatment of urge incontinence. We have found that the compounds of the present invention are very good at elevating PDH activity, a property nowhere disclosed in EP 0617010 and EP 524781.
The present invention is based on the surprising discovery that certain compounds elevate PDH activity, a property of value in the treatment of disease states associated with disorders of glucose utilisation such as diabetes mellitus, obesity, (Curto et al., 1997; Int. J. Obes. 21: 1137-1142), and lactic acidaemia. Additionally the compounds may be expected to have utility in diseases where supply of energy-rich substrates to tissues is limiting such as peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, muscle weakness, hyperlipidaemias and atherosclerosis (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530). A compound that activates PDH may also be useful in treating Alzheimer""s disease (AD) (J Neural Transm (1998) 105, 855-870).
Accordingly the present invention provides a compound of formula (I): 
wherein:
n is 1 or 2;
R1 is chloro, fluoro, bromo, methyl or methoxy;
R2 is selected from one of the following three groups:
i) halo, nitro, hydroxy, amino or cyano;
ii) xe2x80x94X1xe2x80x94R5 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONR6xe2x80x94, xe2x80x94NR6COxe2x80x94, xe2x80x94NR6SO2xe2x80x94 or NR6CONR7xe2x80x94; wherein R6 and R7 are independently hydrogen or C1-4alkyl optionally substituted with one or more A; and R5 is selected from C1-6alkyl optionally substituted with one or more A, C3-7cycloalkyl optionally substituted with one or more A, C3-7cycloalkylC1-6alkyl optionally substituted with one or more A, C2-6alkenyl optionally substituted with one or more A, C2-6alkynyl optionally substituted with one or more A, phenyl optionally substituted with one or more D, phenylC1-6alkyl optionally substituted with one or more D, heteroaryl ring optionally substituted on a ring carbon by one or more D or (heteroaryl ring)C1-6alkyl optionally substituted on a ring carbon with one or more D; wherein said heteroaryl ring is a carbon linked 6-membered ring containing 1-2 nitrogen atoms or a carbon linked 5-membered ring containing 1-3 heteroatoms selected independently from O, N and S; and wherein if said 5-membered heteroaryl ring contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
iii) a nitrogen-linked 4-8 membered heterocyclic group optionally substituted on a ring carbon by one or more D and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
R3 is C1-6alkyl optionally substituted with one or more A, C3-7cycloalkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms optionally substituted on a ring carbon by one or more D, or a carbon linked 5-membered heteroaryl ring containing 1-3 heteroatoms selected independently from O, N and S optionally substituted on a ring carbon by one or more D and wherein if said 5-membered heteroaryl ring contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
A is selected from hydroxy, amino, halo, carboxy, Nxe2x80x94(C1-4alkyl)amino, N,N-di-(C1-4alkyl)amino, carbamoyl and C1-6alkoxy;
D is selected from:
i) xe2x80x94Xaxe2x80x94Rc wherein Xa is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NRdSO2xe2x80x94, xe2x80x94NRdCOxe2x80x94, xe2x80x94NRdCONRexe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRdxe2x80x94; wherein Rd and Re are independently hydrogen or C1-4alkyl optionally substituted with one or more hydroxy or C1-4alkoxy; and Rc is selected from hydrogen or C1-6alkyl optionally substituted with one or more hydroxy or C1-4alkoxy;
ii) a 4-8 membered Het which is optionally substituted on a ring carbon with one or more groups selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl or cyano and wherein if said 4-8 membered Het contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
iii) xe2x80x94Xaxe2x80x94C1-6alkyl-Xbxe2x80x94Wc wherein Xa and Rc are as defined hereinbefore and Xb is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
iv) cyano or halo; and
v) xe2x80x94Xcxe2x80x94Rf wherein Xc is xe2x80x94C(O)xe2x80x94 or xe2x80x94SO2xe2x80x94 and Rf is a nitrogen-linked 4-8 membered heterocyclic group optionally substituted on a ring carbon by one or more groups selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl or cyano and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
G is selected from C1-6alkyl optionally substituted with one or more A, C1-6alkanoyl optionally substituted with one or more A, C1-4alkylsulphonyl optionally substituted with one or more A, C3alkoxycarbonyl optionally substituted with one or more A, carbamoyl, Nxe2x80x94(C1-6alkyl)carbamoyl optionally substituted with one or more A, Nxe2x80x94(C1-6alkyl)2carbamoyl optionally substituted with one or more A and benzoyl optionally substituted with one or more A; and
R4 is hydrogen or fluoro;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
In this specification the term xe2x80x9calkylxe2x80x9d includes both straight and branched chain alkyl groups but references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chain version only. For example, xe2x80x9cC1-6alkylxe2x80x9d includes C1-4alkyl, C2-4alkyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as xe2x80x98propylxe2x80x99 are specific for the straight chained version only and references to individual branched chain alkyl groups such as xe2x80x98isopropylxe2x80x99 are specific for the branched chain version only. The term xe2x80x9chaloxe2x80x9d refers to fluoro, chloro, bromo and iodo.
Suitable values for xe2x80x9ca carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atomsxe2x80x9d include pyridyl, pyrimidyl, pyrazinyl and pyridazinyl. Preferably xe2x80x9ca carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atomsxe2x80x9d is pyridyl. In another aspect of the invention preferably xe2x80x9ca carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atomsxe2x80x9d is pyridazinyl.
Suitable values for xe2x80x9ca carbon-linked 5-membered heteroaryl ring containing 1-3 heteroatomsxe2x80x9d include pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl and triazolyl.
A xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d is a saturated, partially saturated or unsaturated, monocyclic ring containing 4-8 atoms of which at least one is a nitrogen atom with optionally 1-3 further heteroatoms selected independently from O, N and S wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94 and a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. It will be appreciated that in forming this nitrogen link, the nitrogen atom is not quaternised, i.e. a neutral compound is formed. Suitable values for xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d include morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl and triazolyl. Further suitable values for xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d include azetidinyl, morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl and triazolyl. Preferably a xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d is morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl or homopiperazinyl. More preferably a xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d is azetidinyl, morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl or homopiperazinyl. Additional suitable values for xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d include azetidinyl, morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, pyrrolinyl, homopiperazinyl, pyrrolyl, pyrazolyl, pyrazolinyl, inidazolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl and triazolyl. Preferably a xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d is morpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl or homopiperazinyl. More preferably a xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d is azetidinyl, morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, pyrrolinyl or homopiperazinyl. Particularly Rf as a xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d is azetidinyl, morpholino or pyrrolidinyl. Particularly when R2 is a xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d it is thiomorpholino. In another aspect of the invention, particularly when R2 is a xe2x80x9cnitrogen-linked 4-8 membered heterocyclic groupxe2x80x9d it is thiomorpholino, piperazinyl, 1-oxothiomorpholino, 1,1-dioxothiomorpholino or morpholino.
A xe2x80x9cnitrogen-linked 4-6 membered heterocyclic groupxe2x80x9d is a saturated, partially saturated or unsaturated, monocyclic ring containing 4-6 atoms of which at least one is a nitrogen atom with optionally 1-3 further heteroatoms selected independently from O, N and S wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94 and a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. It will be appreciated that in forming this nitrogen link, the nitrogen atom is not quaternised, i.e. a neutral compound is formed. Suitable values for a xe2x80x9cnitrogen-linked 4-6 membered heterocyclic groupxe2x80x9d include azetidinyl, morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl and triazolyl. Preferably a xe2x80x9cnitrogen-linked 4-6 membered heterocyclic groupxe2x80x9d is azetidinyl, morpholino or pyrrolidinyl.
A xe2x80x9cnitrogen-linked 5 or 6 membered heterocyclic groupxe2x80x9d is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one is a nitrogen atom with optionally 1-3 further heteroatoms selected independently from O, N and S wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94 and a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. It will be appreciated that in forming this nitrogen link, the nitrogen atom is not quaternised, i.e. a neutral compound is formed. Suitable values for a xe2x80x9cnitrogen-linked 5 or 6 membered heterocyclic groupxe2x80x9d include morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl and triazolyl. Preferably a xe2x80x9cnitrogen-linked 5 or 6 membered heterocyclic groupxe2x80x9d is morpholino, piperidyl, piperazinyl, pyrrolidinyl, thiomorpholino or pyrrolinyl.
A xe2x80x9cnitrogen-linked 6 membered heterocyclic groupxe2x80x9d is a saturated, partially saturated or unsaturated, monocyclic ring containing 6 atoms of which at least one is nitrogen atom with optionally 1-3 further heteroatoms selected independently from O, N and S wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94 and a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. It will be appreciated that in forming this nitrogen link, the nitrogen atom is not quaternised, i.e. a neutral compound is formed. Suitable values for a xe2x80x9cnitrogen-linked 6 membered heterocyclic groupxe2x80x9d include morpholino, piperidyl, piperazinyl, thiomorpholino.
A xe2x80x9c4-8 membered Hetxe2x80x9d is a saturated, partially saturated or unsaturated monocyclic ring containing 48 atoms including 1-4 heteroatoms selected independently from O, N and S, which may be carbon or nitrogen linked, wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94 and a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. Suitable values for xe2x80x9c4-8 membered Hetxe2x80x9d are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, thienyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 4-pyridone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.
A xe2x80x9c5 or 6 membered Hetxe2x80x9d is a saturated, partially saturated or unsaturated monocyclic ring containing 4-8 atoms including 1-4 heteroatoms selected independently from O, N and S, which may be carbon or nitrogen linked, wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94 and a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. Suitable values for xe2x80x9c5 or 6 membered Hetxe2x80x9d are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, thienyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 4-pyridone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.
Examples of xe2x80x9cC1-6alkoxycarbonylxe2x80x9d include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of xe2x80x9cC1-6alkoxyxe2x80x9d include C1-4alkoxy, methoxy, ethoxy and propoxy. Examples of xe2x80x9cC1-14alkylsulphinylxe2x80x9d include methylsulphinyl and ethylsulphinyl. Examples of xe2x80x9cC1-6alkylsulphonylxe2x80x9d include C1-4alkylsulphonyl, mesyl and ethylsulphonyl. Examples of xe2x80x9cC1-6alkanoylxe2x80x9d include C1-4alkanoyl, propionyl and acetyl. Examples of xe2x80x9cC3-7cycloalkylxe2x80x9d are cyclopropyl and cyclohexyl. Examples of xe2x80x9cC2-6alkenylxe2x80x9d are vinyl, allyl and 1-propenyl. Examples of xe2x80x9cC2-6alkynylxe2x80x9d are ethynyl, 1-propynyl and 2-propynyl. Examples of xe2x80x9cNxe2x80x94(C1-6alkyl)carbamoylxe2x80x9d are methylaminocarbonyl and ethylaminocarbonyl. Examples of xe2x80x9cNxe2x80x94(C1-6alkyl)2carbamoylxe2x80x9d are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of xe2x80x9cNxe2x80x94(C1-4alkyl)aminoxe2x80x9d include methylamino and ethylamino. Examples of xe2x80x9cNxe2x80x94(C1-4alkyl)2aminoxe2x80x9d include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of xe2x80x9cphenylC1-4alkylxe2x80x9d include phenylC1-4alkyl, benzyl and phenethyl. Examples of xe2x80x9cC3-7cycloalkylC1-6alkylxe2x80x9d include cyclopropylmethyl, cyclopentylethyl and 2-cyclohexylpropyl. Examples of xe2x80x9c(heteroaryl ring)C1-6alkylxe2x80x9d include pyridylmethyl, pyrazinylethyl and imidazolylpropyl.
According to a further aspect of the present invention there is provided a compound of formula (I) (as depicted above) wherein:
n is 1 or 2;
R1 is chloro, fluoro, bromo, methyl or methoxy;
R2 is selected from one of the following three groups:
i) halo, nitro, hydroxy, amino or cyano;
ii) xe2x80x94X1xe2x80x94R5 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONR6xe2x80x94, xe2x80x94NR6COxe2x80x94, xe2x80x94NR6SO2xe2x80x94 or NR6CONR7xe2x80x94; wherein R6 and R7 are independently hydrogen or C1-4alkyl optionally substituted with one or more A; and R5 is selected from C1-4alkyl optionally substituted with one or more A, C3-7cycloalkyl optionally substituted with one or more A, C2-6alkenyl optionally substituted with one or more A, C2-6alkynyl optionally substituted with one or more A, phenyl optionally substituted with one or more D, a carbon linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms optionally substituted on a ring carbon by one or more D or a carbon linked 5-membered heteroaryl ring containing 1-3 heteroatoms selected independently from O, N and S optionally substituted on a ring carbon by one or more D and wherein if said 5-membered heteroaryl ring contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
iii) a nitrogen-linked 4-8 membered heterocyclic group optionally substituted on a ring carbon by one or more D and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
R3 is C1-6alkyl optionally substituted with one or more A, C3-7cycloalkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms optionally substituted on a ring carbon by one or more D, or a carbon linked 5-membered heteroaryl ring containing 1-3 heteroatoms selected independently from O, N and S optionally substituted on a ring carbon by one or more D and wherein if said 5-membered heteroaryl ring contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
A is selected from hydroxy, amino, halo, carboxy and C1-6alkoxy;
D is selected from:
i) xe2x80x94Xaxe2x80x94Rc wherein Xa is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NRdSO2xe2x80x94, xe2x80x94NRdCOxe2x80x94, xe2x80x94NRdCONRexe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRdxe2x80x94; wherein Rd and Re are independently hydrogen or C1-4alkyl optionally substituted with one or more hydroxy or C1-4alkoxy; and Rc is selected from hydrogen or C1-4alkyl optionally substituted with one or more hydroxy or C1-4alkoxy;
ii) a 4-8 membered Het which is optionally substituted on a ring carbon with one or more groups selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl or cyano and wherein if said 4-8 membered Het contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
iii) xe2x80x94Xaxe2x80x94C1-6alkyl-Xbxe2x80x94Rc wherein Xa and Rc are as defined hereinbefore and Xb is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94; and
iv) cyano or halo;
G is selected from C1-6alkyl optionally substituted with one or more A, C1-6alkanoyl optionally substituted with one or more A, C1-6alkylsulphonyl optionally substituted with one or more A, C1-6alkoxycarbonyl optionally substituted with one or more A, carbamoyl, Nxe2x80x94(C1-6alkyl)carbamoyl optionally substituted with one or more A, Nxe2x80x94(C1-6alkyl)2carbamoyl optionally substituted with one or more A and benzoyl optionally substituted with one or more A; and
R4 is hydrogen or fluoro;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
Accordingly to an additional aspect of the present invention there is provided a compound of formula (I) (as depicted above) wherein:
n is 1 or 2;
R1 is chloro, fluoro, bromo, methyl or methoxy;
R2 is selected from one of the following three groups:
i) halo, nitro, hydroxy, amino or cyano;
ii) xe2x80x94X1xe2x80x94R5 wherein X1 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, NR6xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONR6xe2x80x94, xe2x80x94NR6COxe2x80x94, xe2x80x94NR6SO2xe2x80x94 or NR6CONR7xe2x80x94; wherein R6 and R7 are independently hydrogen or C1-4alkyl optionally substituted with one or more A; and R5 is selected from C1-4alkyl optionally substituted with one or more A, C3-7cycloalkyl optionally substituted with one or more A, C2-6alkenyl optionally substituted with one or more A, C2-4alkynyl optionally substituted with one or more A, phenyl optionally substituted with one or more D, a carbon linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms optionally substituted on a ring carbon by one or more D or a carbon linked 5-membered heteroaryl ring containing 1-3 heteroatoms selected independently from O, N and S optionally substituted on a ring carbon by one or more D and wherein if said 5-membered heteroaryl ring contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
iii) a nitrogen-linked 4-8 membered heterocyclic group optionally substituted on a ring carbon by one or more D and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
R3 is C1-6alkyl optionally substituted with one or more A, C3-7cycloalkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms optionally substituted on a ring carbon by one or more D, or a carbon linked 5-membered heteroaryl ring containing 1-3 heteroatoms selected independently from O, N and S optionally substituted on a ring carbon by one or more D and wherein if said 5-membered heteroaryl ring contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
A is selected from hydroxy, amino, halo, carboxy, Nxe2x80x94(C1-4alkyl)amino, N,N-di-(C1-4alkyl)amino and C1-6alkoxy;
D is selected from:
i) xe2x80x94Xaxe2x80x94Rc wherein Xa is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NRdSO2xe2x80x94, NRdCOxe2x80x94, xe2x80x94NRdCONRexe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRdxe2x80x94; wherein Rd and Re are independently hydrogen or C1-4alkyl optionally substituted with one or more hydroxy or C1-4alkoxy; and Rc is selected from hydrogen or C1-6alkyl optionally substituted with one or more hydroxy or C1-4alkoxy;
ii) a 4-8 membered Het which is optionally substituted on a ring carbon with one or more groups selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl or cyano and wherein if said 4-8 membered Het contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
iii) xe2x80x94Xaxe2x80x94C1-6alkyl-Xbxe2x80x94Rc wherein Xa and Rc are as defined hereinbefore and Xb is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
iv) cyano or halo; and
v) xe2x80x94Xcxe2x80x94Rf wherein Xc is xe2x80x94C(O)xe2x80x94 or xe2x80x94SO2xe2x80x94 and Rf is a nitrogen-linked 4-8 membered heterocyclic group optionally substituted on a ring carbon by one or more groups selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl or cyano and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G;
G is selected from C1-6alkyl optionally substituted with one or more A, C1-6alkanoyl optionally substituted with one or more A, C1-6alkylsulphonyl optionally substituted with one or more A, C1-6alkoxycarbonyl optionally substituted with one or more A, carbamoyl, Nxe2x80x94(C1-6alkyl)carbamoyl optionally substituted with one or more A, Nxe2x80x94(C1-6alkyl)2Carbamoyl optionally substituted with one or more A and benzoyl optionally substituted with one or more A; and
R4 is hydrogen or fluoro;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
Preferred values of R1, R2, R3 and R4 are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
In one aspect of the invention preferably n is 1.
In another aspect of the invention preferably n is 2.
Preferably R1 is chloro, fluoro or bromo.
More preferably R1 is chloro or fluoro.
Particularly R1 is chloro.
In another aspect of the invention, preferably R1 is methyl, chloro, fluoro or bromo.
In another aspect of the invention, more preferably R1 is methyl, chloro or fluoro.
In another aspect of the invention, particularly R1 is methyl or chloro.
Where R2 is Selected From Group i):
Preferably group i) is halo or hydroxy.
More preferably group i) is halo.
Particularly group i) is chloro or fluoro.
More particularly group i) is chloro.
In Another Aspect of the Invention, Where R2 is Selected From Group i):
Preferably group i) is nitro, halo, amino or hydroxy.
More preferably group i) is nitro, amino or halo.
Particularly group i) is nitro, bromo, iodo, amino, chloro or fluoro.
Where R2 is Selected From Group ii):
Preferably in group ii) X1 is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, NR6 or xe2x80x94NR6COxe2x80x94; preferably R6 is hydrogen; and preferably R5 is selected from C1-6alkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or a carbon linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms optionally substituted on a ring carbon by one or more D.
More preferably in group ii) X1 is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR6COxe2x80x94; more preferably R6 is hydrogen; and more preferably R5 is selected from C1-4alkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or a carbon linked pyridyl optionally substituted on a ring carbon by one or more D.
Particularly in group ii) X1 is xe2x80x94Sxe2x80x94 or xe2x80x94NR6COxe2x80x94; particularly R6 is hydrogen; and particularly R5 is selected from methyl optionally substituted with one or more A, ethyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or a carbon linked pyridyl optionally substituted on a ring carbon by one or more D. In another aspect of the invention, where R2 is selected from group ii):
Preferably in group ii) X1 is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR6xe2x80x94 or xe2x80x94NR6COxe2x80x94; preferably R6 is hydrogen; and preferably R5 is selected from C1-6alkyl optionally substituted with one or more A or phenyl optionally substituted with one or more D.
More preferably in group ii) X1 is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR6COxe2x80x94; more preferably R6 is hydrogen; and more preferably R5 is selected from C1-4alkyl optionally substituted with one or more A or phenyl optionally substituted with one or more D.
Particularly in group ii) X1 is xe2x80x94Sxe2x80x94 or xe2x80x94NR6COxe2x80x94; particularly R6 is hydrogen; and particularly R5 is selected from methyl optionally substituted with one or more A, ethyl optionally substituted with one or more A or phenyl optionally substituted with one or more D.
In another aspect of the invention, where R2 is selected from group ii):
Preferably in group ii) X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, NR6 or xe2x80x94NR6COxe2x80x94; preferably R6 is hydrogen; and preferably R5 is selected from C1-6alkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or phenylC1-6alkyl optionally substituted with one or more D.
More preferably in group ii) X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR6COxe2x80x94; more preferably R6 is hydrogen; and more preferably R5 is selected from C1-4alkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or phenylC1-4alkyl optionally substituted with one or more D.
Where R2 is Selected From Group iii):
Preferably group iii) is a nitrogen-linked 5 or 6 membered heterocyclic group optionally substituted on a ring carbon by one or more D and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G.
More preferably group iii) is a nitrogen-linked 6 membered heterocyclic group optionally substituted on a ring carbon by one or more D and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G.
Particularly group iii) is morpholino optionally substituted on a ring carbon by one or more D, piperidin-1-yl optionally substituted on a ring carbon by one or more D or piperazin-1-yl optionally substituted on a ring carbon by one or more D and optionally substituted on the xe2x80x94NHxe2x80x94 moiety by a group selected from G.
In Another Aspect of the Invention, Where R2 is Selected From Group iii):
Particularly group iii) is morpholino optionally substituted on a ring carbon by one or more D, thiomorpholino optionally substituted on a ring carbon by one or more D, piperidin-1-yl optionally substituted on a ring carbon by one or more D or piperazin-1-yl optionally substituted on a ring carbon by one or more D and optionally substituted on the xe2x80x94NHxe2x80x94 moiety by a group selected from G.
More particularly group iii) is thiomorpholino.
In Another Aspect of the Invention, Where R2 is Selected From Group iii):
Particularly group iii) is morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino or piperazin-1-yl optionally substituted on the xe2x80x94NHxe2x80x94 moiety by a group selected from G.
Preferably A is hydroxy, amino, halo, carboxy and methoxy.
More preferably A is hydroxy.
In another aspect of the invention, preferably A is hydroxy, amino, dimethylamino, halo, carboxy and methoxy.
In another aspect of the invention, more preferably A is hydroxy, methoxy and dimethylamino.
In another aspect of the invention, preferably A is hydroxy, amino, dimethylamino, halo, carboxy, methoxy and carbamoyl.
Where D is Selected From Group i):
Preferably Xa in group i) is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRdxe2x80x94, xe2x80x94NRdCONRexe2x80x94 or xe2x80x94CONRdxe2x80x94; preferably Rd is hydrogen or C1-4alkyl optionally substituted with one or more hydroxy; and preferably Re is selected from hydrogen or C1-6alkyl optionally substituted with one or more hydroxy.
More preferably Xa in group i) is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRdxe2x80x94; more preferably Rd is hydrogen, methyl or ethyl optionally substituted with hydroxy; and more preferably Rc is selected from hydrogen or C14alkyl optionally substituted with one or more hydroxy.
More preferably Xa in group i) is xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRdxe2x80x94; more preferably Rd is hydrogen, methyl or ethyl optionally substituted with hydroxy; and more preferably Rc is selected from hydrogen, methyl or ethyl optionally substituted with hydroxy.
In another aspect of the invention, where D is selected from group i):
Preferably Xa in group i) is xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRdxe2x80x94 or xe2x80x94CONRdxe2x80x94; more preferably Rd is hydrogen, methyl or ethyl optionally substituted with hydroxy; and more preferably Rc is selected from hydrogen, methyl, ethyl or butyl optionally substituted with hydroxy.
Where D is Selected From Group ii):
Preferably group ii) is a 5 or 6 membered Het which is optionally substituted on a ring carbon with one or more groups selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl or cyano and wherein if said 5 or 6 membered Het contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G.
More preferably group ii) is a 5 or 6 membered Het which is optionally substituted on a ring carbon with one or more groups selected from hydroxy, halo, methyl, ethyl, methoxy, ethoxy or cyano and wherein if said 5 or 6 membered Het contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted with a group selected from G.
Particularly group ii) is morpholino, morpholinyl, piperidinyl or piperazinyl optionally substituted on the xe2x80x94NHxe2x80x94 moiety by a group selected from G.
Where D is Selected From Group iii):
Preferably group iii) is xe2x80x94Xaxe2x80x94C2-4alkyl-Xbxe2x80x94Rc wherein Xa and Rc are as defined hereinbefore and Xb is preferably xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94.
Where D is Selected From Group iv):
Preferably group iv) is cyano, fluoro or chloro.
More preferably group iv) is fluoro or chloro.
In Another Aspect of the Invention, Where D is Selected From Group iv):
Preferably group iv) is fluoro.
Where D is Selected From Group v):
Preferably Xc is xe2x80x94C(O)xe2x80x94 and Rf is a nitrogen-linked 4-6 membered heterocyclic group optionally substituted by hydroxy.
More preferably Xc is xe2x80x94C(O)xe2x80x94 and Rf is azetidinyl, morpholino or pyrrolidinyl (optionally substituted by hydroxy).
Particularly Xc is xe2x80x94C(O)xe2x80x94 and Rf is azetidinyl, morpholino or 3-hydroxypyrrolidinyl.
Preferably G is C1-6alkanoyl optionally substituted with one or more A or C1-6alkyl optionally substituted by one or more A.
More preferably G is C1-4alkanoyl optionally substituted with one or more A or C1-4alkyl optionally substituted by one or more A.
Particularly G is acetyl or C2-4alkyl substituted by one or more A.
More particularly G is acetyl.
Preferably R2 is chloro, fluoro, methylthio, acetylamino, hydroxy, C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), phenylsulphonyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)-piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], pyridylsulphonyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), morpholino, 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl.
More preferably R2 is chloro, fluoro, methylthio, acetylamino, hydroxy, methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), phenylsulphonyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-N-ethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, N-ethylcarbamoyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)-piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], pyridylsulphonyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-Nethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, Nethylcarbamoyl (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], methylamino, ethylamino (optionally substituted with hydroxy), morpholino, 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl.
Particularly R2 is chloro, fluoro, methylthio, acetylamino or hydroxy.
In another aspect of the invention, preferably R2 is chloro, fluoro, bromo, iodo, nitro, amino, methylthio, acetylamino, hydroxy, C1-4alkylsulphanyl (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy, methoxy or dimethylamino), phenylsulphonyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)-piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], pyridylsulphonyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), morpholino, 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], thiomorpholino, phenylsulphanyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl) or phenylsulphinyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl).
In a further aspect of the invention preferably R2 is chloro, fluoro, bromo, iodo, nitro, hydroxy, amino, methylthio, acetylamino, C1-4alkylsulphanyl (optionally substituted with hydroxy), C1-4alkylsulphinyl, C1-4alkylsulphonyl, Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy, methoxy or dimethylamino), thiomorpholino, phenylsulphanyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl) or phenylsulphinyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl).
In another aspect of the invention, more preferably R2 is chloro, fluoro, bromo, iodo, nitro, amino, methylthio, acetylamino, hydroxy, methylsulphanyl, ethylsulphanyl (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy, methoxy or dimethylamino), phenylsulphonyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-N-ethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, N-ethylcarbamoyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)-piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], pyridylsulphonyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-N-ethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, Nethylcarbamoyl (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], methylamino, ethylamino (optionally substituted with hydroxy), morpholino, 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], thiomorpholino or phenylsulphanyl [optionally substituted with N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-Nethylcarbamoyl (optionally substituted with hydroxy)].
In another aspect of the invention, particularly R2 is fluoro, chloro, bromo, iodo, nitro, amino, hydroxy, methylthio, ethylsulphinyl, mesyl, 2-hydroxyethylamino, 2-methoxyethylamino, 2-dimethylaminoethylamino, 2,3-dihydroxypropylamino, 2-hydroxyethylsulphanyl, acetylamino, 4-N,N-dimethylcarbamoylphenylsulphanyl, 4-N,N-dimethylcarbamoylphenylsulphinyl or thiomorpholino.
In another aspect of the invention, preferably R2 is chloro, fluoro, bromo, iodo, nitro, amino, methoxy, acetylamino, hydroxy, C1-4alkylsulphanyl (optionally substituted with hydroxy), C1-4alkylsulphinyl, C1-4alkylsulphonyl, Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy, methoxy, dimethylamino or carbamoyl), morpholino, 4-acetylpiperazin-1-yl, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, benzylamino, phenoxy, phenylsulphanyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl) or phenylsulphinyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl).
In another aspect of the invention, more preferably R2 is chloro, fluoro, bromo, iodo, nitro, amino, methoxy, acetylamino, hydroxy, methylthio, 2-hydroxyethylthio, methylsulphinyl, mesyl, 2-hydroxyethylamino, 2-methoxyethylamino, carbamoylmethylamino, 2-dimethylaminoethylamino, 2,3-dihydroxypropylamino, morpholino, 4-acetylpiperazin-1-yl, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, benzylamino, phenoxy, 4-(N,N-dimethylcarbamoyl)phenylsulphanyl or 4-(N,N-dimethylcarbamoyl)phenylsulphinyl.
In another aspect of the invention, particularly R2 is methylthio, morpholino, 4-acetylpiperazin-1-yl, 1-oxothiomorpholino or 1,1-dioxothiomorpholino.
In a further aspect of the invention more preferably R2 is amino, 2-hydroxyethylamino or 2-methoxyethylamino.
In an additional aspect of the invention more preferably R2 is fluoro or chloro.
Preferably R3 is C1-6alkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms optionally substituted on a ring carbon by one or more D.
More preferably R3 is C1-4alkyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or a carbon-linked pyridyl optionally substituted on a ring carbon by one or more D.
Particularly R3 is methyl optionally substituted with one or more A, ethyl optionally substituted with one or more A, phenyl optionally substituted with one or more D or a carbon-linked pyridyl optionally substituted on a ring carbon by one or more D.
Particularly R3 is methyl, ethyl optionally substituted with A, phenyl optionally substituted with one or more D or a carbon-linked pyridyl optionally substituted on a ring carbon by one or more D.
Therefore, in another aspect of the invention preferably R3 is C1-4alkyl optionally substituted with one or more hydroxy, phenyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl], or carbon-linked pyridyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl].
Particularly R3 is methyl, ethyl optionally substituted with hydroxy, phenyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-N-ethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, N-ethylcarbamoyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl] or carbon-linked pyridyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-N-ethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, N-ethylcarbamoyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl].
More particularly R3 is methyl, ethyl optionally substituted with hydroxy, or phenyl (optionally substituted with halo).
Particularly preferred R3 is ethyl or 4-fluorophenyl.
Therefore, in another aspect of the invention preferably R3 is C1-4alkyl (optionally substituted with one or more hydroxy), phenyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)-piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, 4-(2-hydroxypropyl)piperazin-1-yl, azetidinylcarbonyl, morpholinocarbonyl or pyrrolidinylcarbonyl (optionally substituted with hydroxy)], or carbon-linked pyridyl [optionally substituted with halo, amino, Nxe2x80x94(C1-4alkyl)2amino (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)2carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4allyl)carbamoyl (optionally substituted with hydroxy), Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), C1-4alkylsulphinyl (optionally substituted with hydroxy), C1-4alkylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl].
Therefore, in a further aspect of the invention preferably R3 is C1-4alkyl (optionally substituted with one or more hydroxy), phenyl [optionally substituted with halo, Nxe2x80x94(C1-4alkyl)2carbamoyl, Nxe2x80x94(C1-4alkyl)carbamoyl, Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy), C1-4alkylsulphonyl, azetidinylcarbonyl, morpholinocarbonyl or pyrrolidinylcarbonyl (optionally substituted with hydroxy)], or carbon-linked pyridyl [optionally substituted with amino].
Particularly R3 is methyl, ethyl (optionally substituted with hydroxy), butyl (optionally substituted with hydroxy), phenyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-N-ethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, N-ethylcarbamoyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, 4-(2-hydroxypropyl)piperazin-1-yl, azetidinylcarbonyl, morpholinocarbonyl or pyrrolidinylcarbonyl (optionally substituted with hydroxy)] or carbon-linked pyridyl [optionally substituted with halo, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted with hydroxy), N-methyl-N-ethylcarbamoyl (optionally substituted with hydroxy), N-methylcarbamoyl, N-ethylcarbamoyl (optionally substituted with hydroxy), methylamino, ethylamino (optionally substituted with hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted with hydroxy), N-methyl-N-ethylamino (optionally substituted with hydroxy), methylsulphinyl, ethylsulphinyl (optionally substituted with hydroxy), mesyl, ethylsulphonyl (optionally substituted with hydroxy), 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl or 4-(2-hydroxypropyl)piperazin-1-yl).
More particularly R3 is methyl, ethyl, 2-hydroxyethyl, 2-hydroxybutyl, 4-fluorophenyl, 4-mesylphenyl, 4-(2-hydroxyethylamino)phenyl, 4-(N-methylcarbamoyl)phenyl, 4-(N-ethylcarbamoyl)phenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-(N-methyl-N-ethylcarbamoyl)phenyl, 4-(azetidinylcarbonyl)phenyl, 4-(morpholinocarbonyl)phenyl, 4-(3-hydroxypyrrolidinylcarbonyl)phenyl or 6-aminopyrid-2-yl.
In another aspect of the invention particularly R3 is methyl, ethyl (optionally substituted with hydroxy), isopropyl, butyl (optionally substituted with hydroxy), phenyl [optionally substituted with halo, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, ethylamino (optionally substituted with hydroxy), mesyl, azetidinylcarbonyl, morpholinocarbonyl or pyrrolidinylcarbonyl (optionally substituted with hydroxy)] or carbon-linked pyridyl [optionally substituted with amino].
In another aspect of the invention more particularly R3 is methyl, ethyl, 2-hydroxyethyl, isopropyl, 2-hydroxybutyl, 4-fluorophenyl, 4-(2-hydroxyethylamino)phenyl, 4-mesylphenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-(N-ethylcarbamoyl)phenyl, 4-(N-methyl-N-ethylcarbamoyl)phenyl, 4-(N-methylcarbamoyl)phenyl, 4-(azetidinylcarbonyl)phenyl, 4-(morpholinocarbonyl)phenyl, 4-(3-hydroxypyrrolidinylcarbonyl)phenyl or 2-aminopyrid-6-yl.
In another aspect of the invention more particularly preferred R3 is methyl, ethyl or isopropyl.
In a further aspect of the invention more particularly preferred R3 is 4-(N-methylcarbamoyl)phenyl or 4-(N,N-dimethylcarbamoyl)phenyl.
In a further aspect of the invention especially particularly preferred R3 is 4-(N,N-dimethylcarbamoyl)phenyl.
In one aspect of the invention, preferably R4 is hydrogen.
In another aspect of the invention, preferably R4 is fluoro.
At the xe2x80x94C(OH)(Me)(CF3) chiral center, the R-configuration is generally the preferred stereochemistry.
Therefore in another aspect of the invention, there is provided a compound of the formula (I) as depicted above wherein:
n is 1 or 2;
R1 is methyl, chloro or fluoro,
R2 is chloro, fluoro, bromo, iodo, nitro, amino, methoxy, acetylamino, hydroxy, C1-4alkylsulphanyl (optionally substituted with hydroxy), C1-4alkylsulphinyl, C1-4alkylsulphonyl, Nxe2x80x94(C1-4alkyl)amino (optionally substituted with hydroxy, methoxy, dimethylamino or carbamoyl), morpholino, 4-acetylpiperazin-1-yl, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, benzylamino, phenoxy, phenylsulphanyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl) or phenylsulphinyl (optionally substituted with Nxe2x80x94(C1-4alkyl)2carbamoyl);
R3 is methyl, ethyl (optionally substituted with hydroxy), isopropyl, butyl (optionally substituted with hydroxy), phenyl [optionally substituted with halo, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, ethylamino (optionally substituted with hydroxy), mesyl, azetidinylcarbonyl, morpholinocarbonyl or pyrrolidinylcarbonyl (optionally substituted with hydroxy)] or carbon-linked pyridyl [optionally substituted with amino]; and
R4 is hydrogen;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
Therefore in another aspect of the invention, there is provided a compound of the formula (I) as depicted above wherein:
n is 2;
R1 is chloro;
R2 is methylthio, morpholino, 4-acetylpiperazin-1-yl, 1-oxothiomorpholino or 1,1-dioxothiomorpholino;
R3 is methyl, ethyl or isopropyl;
R4 is hydrogen;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
A preferred compound of the invention is any one of the Examples or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
More preferred compounds of the invention are Examples 7, 8, 22, 23, 24, 28, 48, 64, 69, 70, 74, 75 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
In another aspect of the invention, more preferred compounds of the invention are Examples 32, 35 and 61 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
In a further aspect of the invention more preferred compounds of the invention are Examples 17, 18 and 58 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
Preferred aspects of the invention are those which relate to the compound or a pharmaceutically acceptable salt thereof.
Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which elevates PDH activity and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein.
It will be appreciated by those skilled in the art that certain compounds of formula (I) contain one or more asymmetrically substituted carbon and/or sulphur atoms, and accordingly may exist in, and be isolated as enantiomerically pure, a mixture of diastereoisomers or as a racemate. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, enantiomerically pure, mixture of diastereoisomers, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the elevation of PDH activity, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, (for example WO 9738124), by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the elevation of PDH activity by the standard tests described hereinafter.
It is also to be understood that certain compounds of the formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which elevate PDH activity.
A compound of the formula (I), or salt thereof, and other compounds of the invention (as hereinafter defined) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes include, for example, those illustrated in European Patent Applications, Publication Nos. 0524781, 0617010, 0625516, and in GB 2278054, WO 9323358 and WO 9738124.
Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, which process (in which variable groups are as defined for formula (I) unless otherwise stated) comprises of:
(a) deprotecting a protected compound of formula (II): 
where Pg is an alcohol protecting group;
(b) oxidising a compound of formula (III): 
(c) coupling compounds of formula (IV): 
with an acid of formula (V): 
wherein X is OH;
(d) coupling an aniline of formula (IV) with an activated acid derivative of formula (V); and thereafter if necessary:
i) converting a compound of the formula (I) into another compound of the formula (I);
ii) removing any protecting groups; or
iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
Suitable values for Pg are a benzyl group, a silyl group (for example a trialkylsilyl group or an alkyldiphenylsilyl group) or an acetyl protecting group.
Where formula (V) is an activated acid derivative, suitable values for X include halo (for example chloro or bromo), anhydrides, aryloxys (for example 4-nitrophenoxy or pentafluorophenoxy) or imidazol-1-yl.
Specific conditions of the above reactions are as follows:
Process a)
Examples of suitable reagents for deprotecting an alcohol of formula (II) are:
1) when Pg is benzyl:
(i) hydrogen in the presence of palladium/carbon catalyst, i.e. hydrogenolysis; or
(ii) hydrogen bromide or hydrogen iodide;
2) when Pg is a silyl protecting group:
(i) tetrabutylammonium fluoride; or
(ii) aqueous hydrofluoric acid;
3) when Pg is acetyl:
i) mild aqueous base for example lithium hydroxide; or
ii) ammonia or an amine such as dimethylamine.
The reaction can be conducted in a suitable solvent such as EtOH, MeOH, acetonitrile, or DMSO and may conveniently be performed at a temperature in the range of 40 to 100xc2x0 C.
Compounds of formula (II) may be prepared according to the following scheme: 
E is a carboxy protecting group. Suitable values for E include C1-6alkyl, such as methyl and ethyl.
Compounds of formula (IIa) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. The synthesis of compounds of formula (IV) is described below.
Process b)
Suitable oxidising agents include potassium permanganate, OXONE, sodium periodate, tert-butyl hydroperoxide (as solution in toluene), peracids (such as for example 3-chloroperoxybenzoic acid), hydrogen peroxide, TPAP (tetrapropylammonium perruthenate) or oxygen. The reaction may be conducted in a suitable solvent such as ether, DCM, MeOH, EtOH, water, acetic acid, or mixtures of two or more of these solvents. The reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 100xc2x0 C.
Compounds of formula (III) may be prepared according to the following schemes: 
The skilled reader will appreciate that the order of steps 1 and 2 in Scheme 2 may be reversed. 
wherein M is an alkali metal. Suitable values for M include lithium, sodium or potassium.
X is a leaving group, suitable values for X include halo, mesyl and tosyl. 
X is a leaving group, suitable values for X include halo, mesyl and tosyl.
Compounds of formula (IIIa) and (IIId) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
Process c)
The reaction can be conducted in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, for example conditions such as those described above for the coupling of (IId) and (IV), or for example dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di-alkyl-pyridines (such as 2,6-lutidine or 2,6-di-tert-butylpyridine) or 2,6-diphenylpyridine. Suitable solvents include DMA, DCM, benzene, THF, and DMF. The coupling reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 40xc2x0 C.
Compounds of formula (IV) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art, for example they may be prepared by oxidising compounds of formula (IIIf) (with the aniline protected with a suitable protecting group) under standard oxidation conditions, for example with hydrogen peroxide or meta-chloroperoxybenzoic acid (followed by de-protection), or they may be prepared according to the following scheme: 
Compounds of formula (IVa) and (V) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
If the resolved acid of formula (V) is required it may be prepared by any of the known methods for preparation of optically-active forms (for example, by recrystallization of the chiral salt {for example WO 9738124}, by enzymatic resolution or by chromatographic separation using a chiral stationary phase). For example if an (R)-(+) resolved acid is required it may be prepared by the method of Scheme 2 in World Patent Application Publication No. WO 9738124 for preparation of the (S)-(xe2x88x92) acid, i.e. using the classical resolution method described in European Patent Application Publication No. EP 0524781, also for preparation of the (S)-(xe2x88x92) acid, except that (1S,2R)-norephedrine may be used in place of (S)-(xe2x88x92)-1-phenylethylamine. The chiral acid may also be prepared by using the enzymatic resolution method as described in Tetrahedron Asymmetry, 1999, 10, 679.
Process d)
This coupling may be achieved optionally in the presence of a base for example triethylamine, pyridine, 2,6-di-alkyl-pyridines (such as 2,6-lutidine or 2,6-di-tert-butylpyridine) or 2,6diphenylpyridine. Suitable solvents include DMA, DCM, benzene, THF, and DMF. The coupling reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 40xc2x0 C.
If not commercially available, the necessary starting materials for the procedures such as that described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples.
For example, it will be appreciated that certain of the optional aromatic substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications or interconversions either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acylhalide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl using, for example, hydrogen peroxide in acetic acid with heating or 3-chloroperbenzoic acid. Particular examples of functional group interconversions are for example conversion of an aniline into a halophenyl by, for example, diazotization in the presence of cupurous halides.
It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as, for example hydrochloric, sulphuric or phosphoric acid or TFA and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as TFA, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
In cases where compounds of formula (I) are sufficiently basic or acidic to form stable acid or basic salts, administration of the compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following. Examples of suitable pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiologically acceptable anion, for example, tosylate, methanesulphonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, xcex1-ketoglutarate, and xcex1-glycerophosphate. Suitable inorganic salts may also be formed such as sulphate, nitrate, and hydrochloride.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound of formula (I) (or its ester) with a suitable acid affording a physiologically acceptable anion. It is also possible with most compounds of the invention to make a corresponding alkali metal (e.g. sodium, potassium, or lithium) or alkaline earth metal (e.g. calcium) salt by treating a compound of formula (I) (and in some cases the ester) with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g. the ethoxide or methoxide) in aqueous medium followed by conventional purification techniques.
The compounds of the formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I). Examples of prodrugs include in vivo hydrolysable esters of a compound of the formula (I).
An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
Suitable in vivo hydrolysable esters for a compound of the formula (I) containing a carboxy group include C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
Suitable in vivo hydrolysable esters of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers.
Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Other in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents for benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
In vivo cleavable prodrugs of compounds of formula (I) also include in vivo hydrolysable amides of compounds of the formula (I) containing a carboxy group, for example, a Nxe2x80x94C1-4alkyl or N-di-C1-6alkyl amide such as N-methyl, N-ethyl, N-propyl, N-dimethyl, N-ethyl-N-methyl or N-diethyl amide.
The identification of compounds which elevate PDH activity is the subject of the present invention. These properties may be assessed, for example, using one or more of the procedures set out below:
(a) In Vitro Elevation of PDH Activity
This assay determines the ability of a test compound to elevate PDH activity. cDNA encoding PDH kinase may be obtained by Polymerase Chain Reaction (PCR) and subsequent cloning. This may be expressed in a suitable expression system to obtain polypeptide with PDH kinase activity. For example rat PDHkinaseII (rPDHKII) obtained by expression of recombinant protein in Escherichia coli (E. Coli), was found to display PDH kinase activity.
In the case of the rPDHKII (Genbank accession number U10357) a 1.3 kb fragment encoding the protein was isolated by PCR from rat liver cDNA and cloned into a vector (for example pQE32xe2x80x94Quiagen Ltd.). The recombinant construct was transformed into E. coli (for example M15pRep4xe2x80x94Quiagen Ltd.). Recombinant clones were identified, plasmid DNA was isolated and subjected to DNA sequence analysis. One clone which had the expected nucleic acid sequence was selected for the expression work. Details of the methods for the assembly of recombinant DNA molecules and the expression of recombinant proteins in bacterial systems can be found in standard texts for example Sambrook et al, 1989, Molecular Cloningxe2x80x94A Laboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press. Other known PDH kinases for use in assays, may be cloned and expressed in a similar manner.
For expression of rPDHKII activity, E. coli strain M15pRep4 cells were transformed with the pQE32 vector containing rPDHKII cDNA. This vector incorporates a 6-His tag onto the protein at its N-terminus. E. coli were grown to an optical density of 0.6 (600 nM) and protein expression was induced by the addition of 10 xcexcM isopropylthio-xcex2-galactosidase. Cells were grown for 18 hours at 18xc2x0 C. and harvested by centrifugation. The resuspended cell paste was lysed by homogenisation and insoluble material removed by centrifugation at 24000xc3x97g for 1 hour. The 6-His tagged protein was removed from the supernatant using a nickel chelating nitrilotriacetic acid resin (Ni-NTA: Quiagen Ltd.) matrix (Quiagen) which was washed with 20 mM tris(hydroxymethyl)aminomethane-hydrogen chloride, 20 mM imidazole, 0.5 M sodium chloride pH 8.0, prior to elution of bound protein using a buffer containing 20 mM tris(hydroxymethyl)aminomethane-hydrogen chloride, 200 mM imidazole, 0.15 M sodium chloride pH 8.0. Eluted fractions containing 6-His protein were pooled and stored in aliquots at xe2x88x9280xc2x0 C in 10% glycerol.
Each new batch of stock enzyme was titrated in the assay to determine a concentration giving approximately 90% inhibition of PDH in the conditions of the assay. For a typical batch, stock enzyme was diluted to 7.5 xcexcg/ml.
For assay of the activity of novel compounds, compounds were diluted with 10% DMSO and 10 xcexcl transferred to individual wells of 96-well assay plates. Control wells contained 20 xcexcl 10% DMSO instead of compound. 40 xcexcl Buffer containing 50 mM potassium phosphate buffer pH 7.0, 10 mM ethylene glycol-bis(xcex2-aminoethyl ether)-N,N-tetracetic acid (EGTA), 1 mM benzamidine, 1 mM phenylmethylsulphonyl fluoride (PMSF), 0.3 mM tosyl-L-lysine chloromethyl ketone (TLCK), 2 mM dithiothreitol (DTT), recombinant rPDHKII and compounds were incubated in the presence of PDH kinase at room temperature for 45 minutes. In order to determine the maximum rate of the PDH reaction a second series of control wells were included containing 10% DMSO instead of compound and omitting rPDHKII. PDH kinase activity was then initiated by the addition of 5 xcexcM ATP, 2 mM magnesium chloride and 0.04 U/ml PDH (porcine heart PDH Sigma P7032) in a total volume of 50 xcexcl and plates incubated at ambient temperature for a further 45 minutes. The residual activity of the PDH was then determined by the addition of substrates (2.5 mM coenzyme A, 2.5 mM thiamine pyrophosphate (cocarboxylase), 2.5 mM sodium pyruvate, 6 mM NAD in a total volume of 80 xcexcl and the plates incubated for 90 minutes at ambient temperature. The production of reduced NAD (NADH) was established by measured optical density at 340 nm using a plate reading spectrophotometer. The ED50 for a test compound was determined in the usual way using results from 12 concentrations of the compound.
(b) In Vitro Elevation of PDH Activity in Isolated Primary Cells
This assay determines the ability of compounds to stimulate pyruvate oxidation in primary rat hepatocytes.
Hepatocytes were isolated by the two-step collagenase digestion procedure described by Seglen (Methods Cell Biol. (1976) 13, 29-33) and plated out in 6-well culture plates (Falcon Primaria) at 600000 viable cells per well in Dulbecco""s Modified Eagles Medium (DMEM, Gibco BRL) containing 10% foetal calf serum (FCS), 10% penicillin/streptomycin (Gibco BRL) and 10% non-essential amino acids (NEAA, Gibco BRL). After 4 hours incubation at 37xc2x0 C. in 5% CO2, the medium was replaced with Minimum Essential Medium (MEM, Gibco BRL) containing NEAA and penicillin/streptomycin as above in addition to 10 nM dexamethasone and 10 nM insulin.
The following day cells were washed with phosphate buffered saline (PBS) and medium replaced with 1 ml HEPES-buffered Krebs solution (25 mM HEPES, 0.15M sodium chloride, 25 mM sodium hydrogen carbonate, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium sulphate, 1 mM potassium dihydrogen phosphate) containing the compound to be tested at the required concentration in 0.1% DMSO. Control wells contained 0.1% DMSO only and a maximum response was determined using a 10 xcexcM treatment of a known active compound. After a preincubation period of 40 minutes at 37xc2x0 C. in 5% CO2, cells were pulsed with sodium pyruvate to a final concentration of 0.5 mM (containing 1-14C sodium pyruvate (Amersham product CFA85) 0.18 Ci/mmole) for 12 minutes. The medium was then removed and transferred to a tube which was immediately sealed with a bung containing a suspended centre well. Absorbent within the centre well was saturated with 50% phenylethylamine, and CO2 in the medium released by the addition of 0.2 xcexcl 60% (w/v) perchloric acid (PCA). Released 14CO2 trapped in the absorbent was determined by liquid scintillation counting. The ED50 for a test compound was determined in the usual way using results from 7 concentrations of the compound.
(c) In Vivo Elevation of PDH Activity
The capacity of compounds to increase the activity of PDH in relevant tissues of rats may be measured using the test described hereinafter. Typically an increase in the proportion of PDH in its active, nonphosphorylated form may be detected in muscle, heart, liver and adipose tissue after a single administration of an active compound. This may be expected to lead to a decrease in blood glucose after repeated administration of the compound. For example a single administration of DCA, a compound known to activate PDH by inhibition of PDH kinase (Whitehouse, Cooper and Randle (1974) Biochem. J. 141, 761-774) 150 mg/kg, intraperitoneally, increased the proportion of PDH in its active form (Vary et al. (1988) Circ. Shock 24, 3-18) and after repeated administration resulted in a significant decrease in plasma glucose (Evans and Stacpoole (1982) Biochem. Pharmacol.31, 1295-1300).
Groups of rats (weight range 140-180 g) are treated with a single dose or multiple doses of the compound of interest by oral gavage in an appropriate vehicle. A control group of rats is treated with vehicle only. At a fixed time after the final administration of compound, animals are terminally anaesthetised, tissues are removed and frozen in liquid nitrogen. For determination of PDH activity, muscle samples are disrupted under liquid nitrogen prior to homogenisation by one thirty-second burst in a Polytron homogenizer in 4 volumes of a buffer containing 40 mM potassium phosphate pH 7.0, 5 mM EDTA, 2 mM DTT, 1% Triton X-100, 10 mM sodium pyruvate, 10 xcexcM phenylmethylsulphonyl chloride (PMSF) and 2 xcexcg/ml each of leupeptin, pepstain A and aprotinin. Extracts are centrifuged before assay. A portion of the extract is treated with PDH phosphatase prepared from pig hearts by the method of Siess and Wieland (Eur. J. Biochem (1972) 26, 96): 20 xcexcl extract, 40 xcexcl phosphatase (1:20 dilution), in a final volume of 125 xcexcl containing 25 mM magnesium chloride, 1 mM calcium chloride. The activity of the untreated sample is compared with the activity of the dephosphorylated extract thus prepared. PDH activity is assayed by the method of Stansbie et al., (Biochem. J. (1976) 154, 225). 50 xcexcl Extract is incubated with 0.75 mM NAD, 0.2 mM CoA, 1.5 mM thiamine pyrophosphate (TPP) and 1.5 mM sodium pyruvate in the presence of 20 xcexcg/ml p-(p-amino-phenylazo) benzene sulphonic acid (AABS) and 50 mU/ml arylamine transferase (AAT) in a buffer containing 100 mM tris(hydroxymethyl)aminomethane, 0.5 mM EDTA, 50 mM sodium fluoride, 5 mM 2-mercaptoethanol and 1 mM magnesium chloride pH 7.8. AAT is prepared from pigeon livers by the method of Tabor et al. (J. Biol. Chem. (1953) 204, 127). The rate of acetyl CoA formation is determined by the rate of reduction of AABS which is indicated by a decrease in optical density at 460 nm.
Liver samples are prepared by an essentially similar method, except that sodium pyruvate is excluded from the extraction buffer and added to the phosphatase incubation to a final concentration of 5 mM.
Treatment of an animal with an active compound results in an increase in the activity of PDH complex in tissues. This is indicated by an increase in the amount of active PDH (determined by the activity of untreated extract as a percentage of the total PDH activity in the same extract after treatment with phosphatase).
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) as defined hereinbefore or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with a pharmaceutically acceptable excipient or carrier.
The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream or for rectal administration for example as a suppository. In general the above compositions may be prepared in a conventional manner using conventional excipients.
The compositions of the present invention are advantageously presented in unit dosage form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
According to a further aspect of the present invention there is provided a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have found that compounds of the present invention elevate PDH activity and are therefore of interest for their blood glucose-lowering effects.
A further feature of the present invention is a compound of formula (I) and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof for use as a medicament.
Conveniently this is a compound of formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for use as a medicament for producing an elevation of PDH activity in a warm-blooded animal such as a human being.
Particularly this is a compound of formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for use as a medicament for treating diabetes mellitus in a warm-blooded animal such as a human being.
In another aspect of the invention, particularly this is a compound of formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for use as a medicament for treating diabetes mellitus, peripheral vascular disease and myocardial ischaemia in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof in the manufacture of a medicament for use in the production of an elevation of PDH activity in a warn-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof in the manufacture of a medicament for use in the treatment of diabetes mellitus in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or an in viva hydrolysable ester thereof in the manufacture of a medicament for use in the treatment of diabetes mellitus, peripheral vascular disease and myocardial ischaemia in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method for producing an elevation of PDH activity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined hereinbefore.
According to a further feature of the invention there is provided a method of treating diabetes mellitus in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined hereinbefore.
According to a further feature of the invention there is provided a method of treating diabetes mellitus, peripheral vascular disease and myocardial ischaemia in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined hereinbefore.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
The elevation of PDH activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. For example in the treatment of diabetes mellitus chemotherapy may include the following main categories of treatment:
i) insulin;
ii) insulin secretagogue agents designed to stimulate insulin secretion (for example glibenclamide, tolbutamide, other sulphonylureas);
iii) oral hypoglycaemic agents such as metformin, thiazolidinediones;
iv) agents designed to reduce the absorption of glucose from the intestine (for example acarbose);
v) agents designed to treat complications of prolonged hyperglycaemia;
vi) other agents used to treat lactic acidaemia;
vii) inhibitors of fatty acid oxidation;
viii) lipid lowering agents;
ix) agents used to treat coronary heart disease and peripheral vascular disease such as aspirin, pentoxifylline, cilostazol; and/or
x) thiamine.
As stated above the compounds defined in the present invention are of interest for their ability to elevate the activity of PDH. Such compounds of the invention may therefore be useful in a range of disease states including diabetes mellitus, peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, myocardial ischaemia, cerebral ischaemia and reperfusion, muscle weakness, hyperlipidaemias, Alzheimer""s disease and/or atherosclerosis. Alternatively such compounds of the invention may be useful in a range of disease states including peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, myocardial ischaemia, cerebral ischaemia and reperfusion, muscle weakness, hyperlipidaemias, Alzheimer""s disease and/or atherosclerosis in particular peripheral vascular disease and myocardial ischaemia.
In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of elevators of PDH activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.